Heart failure (HF) is a major health problem with a high annual mortality rate in the US. The incidence of HF continues to rise despite medical progress in heart failure interventions. Depression is an important psychosocial predictor of HF, with a 2 to 3-fold risk of increased mortality. To understand the role of depression in HF morbidity and mortality, there is a need to determine pathophysiological mechanisms linking depression to HF outcomes. Inflammatory processes play a primary pathophysiologic role in HF, and there is substantial overlap between inflammatory markers related to adverse HF outcomes and those known to be increased in depression. Using a prospective design, the proposed research will determine the role of pro-inflammatory markers (IL6, TNFa, CRP) as measures linking depression to heart failure progression. Two hundred heart failure patients will be monitored repeatedly for depression and inflammatory markers for 2 years. This study will: (1) determine the association between depression and inflammation and the role of neurohormones (catecholamines and cortisol) in this relationship;and (2) determine whether inflammatory processes play a role in the pathophysiological pathways linking depression to adverse heart failure outcome (mortality and HF-related hospitalization). Unique to this study is the use of repeated measures to document the temporal associations between depression and inflammatory markers. Such assessments are important to disentangle whether depression precedes, coincides with, or follows inflammation in heart failure patients. Information from this research will provide important knowledge for patient risk stratification, will elucidate pathophysiological mechanisms by which depression increases risk of adverse heart failure outcomes, and may lead to novel treatment targets in patients at high-risk of life- threatening heart failure complications. Lay language: Heart failure is a serious health problem, with a high mortality rate. Many patients with heart failure also suffer from depression, and these patients are at a substantially greater risk of being hospitalized or dying. This study examines the role of inflammation and immune pathways by which depression results in poor heart failure outcomes. This knowledge will help identify high risk patients and may lead to potential new treatments for depressed heart failure patients.